Oral dosing of many materials with desirable properties and functions can be problematic when provided in a chewable form because the intrinsic taste of such materials can be unpleasant, particularly to children. The intrinsic bitterness of certain active pharmaceutical ingredients (APIs) in particular can present a major obstacle to the acceptance, compliance, and effectiveness of treatments including oral, chewable dosing.
Previous approaches to addressing the problem of poor palatability of certain materials have been based mainly on nullifying undesirable tastes using flavor additives, chemical chelation (e.g., using ion exchange resins and β-cyclodextrins) and physical encapsulation. These systems can be adapted into solid dosage forms or liquid based formulations as solutions, suspensions, or multi-phase emulsions.
Generally, most children cannot swallow traditional solid dosage forms (e.g., tablets and capsules) at least until the age of six due to the risk of choking. For young children (i.e., <2 years of age), liquid dosage forms are preferred as dosing can be facilitated via an oral syringe or spoon. These dosage forms, however, can be problematic as they accentuate the taste issue of bitter active ingredients in solution. Suspensions can improve taste-masking effectiveness, however, mouth feel and grittiness is often the overriding issue.
Alternative non-liquid formulations have been designed to compensate for the poor dosing acceptability and taste limitation of liquid-based formulations for older children (>2 years of age). These formulations typically can include chewable tablets, gummies, specially compounded lollipops, and other confectionary mimics.
Gummy dosage forms are particularly effective for enabling compliant dosing in children as they provide a palatable, chewable base and can incorporate active ingredient(s) that are generally of very low dose, have the ability to withstand the high thermal stress of the gummy manufacturing process, and have low intrinsic taste response. Moreover, while gummy dosage forms provide the basis for effective dosing of active ingredients to children, their application for the delivery of APIs and like materials has been highly restrictive due to the limited number of active ingredients that are compatible with the gummy dosage-platform.
Gummy dosage forms have previously been produced by compounding a variety of ingredients (e.g., sugars, corn syrup, water, gelatin, flavors, and other sweeteners) then cooking the mixture at high temperatures (e.g., up to about 240° C.) before depositing the cooked mixture into preformed molds. The incorporation of the active ingredients can be facilitated only during the initial compounding step prior to cooking. The viscosity of the cooked mixture is generally too high to enable the active ingredients to be added retrospectively. As a result of the very high thermal stress of the cooking process, the active ingredients can be subject to significant chemical and/or physical degradation during the manufacture of gummies. Accordingly, the practice of utilizing overages (including excess active ingredient to off-set the losses due to degradation during manufacturing) has been instituted.
The use of overages to off-set gross manufacturing losses in gummy dosage forms is permitted only for some functional actives that do not present safety concerns. The application of this practice for APIs is not generally feasible as it may lead to significant efficacy, safety, and regulatory issues. In addition, as the quality control requirements for APIs (i.e., claimed dose of active, content uniformity, degradation limits, etc.) are generally much more stringent than food-based functional additives, the suitability of gummies as an oral delivery platform becomes even more prohibitive. As such, there remains a need in the art for oral, chewable dosage forms suitable for delivery of APIs and the like in a manner where active ingredient content can be closely controlled throughout manufacturing to provide a resulting dosage form of consistent quality and desirable palatability.